Abstract

OBJECTIVES: The goals were to determine whether there has been an increase in the rate of venous thromboembolism (VTE) in pediatric tertiary care hospitals and to evaluate the use of anticoagulants in the treatment of hospitalized pediatric patients with VTE.

METHODS: A retrospective cohort study of patients <18 years of age who were discharged from 35 to 40 children's hospitals (depending on the year) across the United States in 2001–2007 was performed. By using the Pediatric Health Information System administrative database, cases were assessed for discharge diagnosis codes for VTE; the use of anticoagulants was assessed by using patient-specific pharmacy files.

RESULTS: During the 7-year study period, in which 11337 hospitalized patients were diagnosed with VTE, the annual rate of VTE increased by 70%, from 34 to 58 cases per 10000 hospital admissions (P < .001). This increase was observed in neonates, infants, children, and adolescents. The majority (63%) of children with VTE had ≥1 coexisting chronic complex medical condition. Pediatric malignancy was the medical comorbid condition associated most strongly with recurrent VTE (P < .001). The proportion of children with VTE who were treated with enoxaparin increased from 29% to 49% during this time period (P < .001); the use of warfarin decreased slightly from 11.4% to 9.6% (P = .02). Increasing age was associated with increased likelihood of patients with VTE being treated with either enoxaparin or warfarin.

CONCLUSION: This multicenter study demonstrates a dramatic increase in the diagnosis of VTE at children's hospitals from 2001 to 2007.

Many authors have suggested that there has been an increase in the rate of venous thromboembolism (VTE) in children; some have even called this a new epidemic in pediatric tertiary care hospitals.1–7 Most speculate, on the basis of known risk factors for VTE in children, that this increase is related to advancements in the treatment and supportive care of critically ill children who previously would not have survived.1–3, 5, 7 Interestingly, there are no published studies that confirm this perceived increase over time.

Epidemiological studies of the incidence of VTE in children are sparse. The most frequently cited incidence among children 1 month to 18 years of age is 0.07 case per 10000 children, increasing to 5.3 cases per 10000 pediatric hospital admissions.1, 2 These estimates are based on a report from the Canadian Registry on 137 patients with VTE identified in 1990–1992.5 The report described the first large observational cohort of pediatric patients with thrombosis and greatly enhanced the understanding of risk factors associated with pediatric VTE. A 2-year study of VTE in the Netherlands in 1997–1998 estimated an incidence of 0.14 case per 10000 children, although that study included neonates.8 To define more clearly the rate of VTE among hospitalized children in the United States and to evaluate how the rate has changed over time, we performed a retrospective cohort study of pediatric patients diagnosed as having VTE in children's hospitals throughout the United States in 2001–2007, by using the Pediatric Health Information System (PHIS) database.

METHODS

Institutional Review Board Evaluation

This study was submitted to the institutional review board of the Children's Hospital of Philadelphia and was determined to be exempt from review.

Data Source

The PHIS is an administrative database that contains comprehensive inpatient data from not-for-profit, tertiary care hospitals throughout the United States. These noncompeting hospitals belong to the Child Health Corporation of America (Shawnee Mission, KS), a business alliance of freestanding children's hospitals. The database is managed by Solucient (Evanston, IL). Participating hospitals provide discharge data including patient demographic data, diagnoses, and procedure codes. Many of the hospitals also submit resource utilization data, including data on medication use. Data are deidentified and undergo a number of reliability and validity checks before being included.

Forty-one hospitals contributed to the PHIS database between January 1, 2001, and December 31, 2007, although all hospitals did not contribute each year; 2001 was the initial time point because this was the first year with complete robust data. Year-specific hospital records were excluded if a hospital did not provide resource utilization data, if individual patients could not be identified throughout the 7-year study period by using a unique medical identification number, or if there were problems regarding data quality. In our final dataset, 35 hospitals were included in 2001 and 2002, 37 in 2003, 39 in 2004, 40 in 2005 and 2006, and 39 in 2007.

Subjects

The source population included pediatric patients (through 18 years of age) who were admitted to PHIS hospitals between January 1, 2001, and December 31, 2007. Subjects with VTE were identified if they had a discharge diagnosis of nonsuperficial venous thrombosis, on the basis of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The ICD-9-CM codes used were 325, 415.1, 415.11, 415.12, 415.19, 451.1, 451.11, 451.19, 451.2, 451.8, 451.81, 451.83, 451.84, 451.89, 451.9, 452, 453.0, 453.1, 453.2, 453.3, 453.41, 453.42, 453.8, 453.9, 557.0, and 572.1. Unique patient identifiers were used, so that it was possible to determine whether a patient had >1 admission with the diagnosis of VTE; such patients were classified as having recurrent VTE.

Demographic Characteristics

Age at admission, gender, race, and ethnicity were recorded for all admissions. We classified age into the following categories: birth to 1 month, 1 month to <1 year, 1 to <6 years, 6 to <13 years, and 13 to 18 years. These categories were chosen so that the rates of VTE in clinically relevant groups (neonates, infants, children, and adolescents) could be compared. Information on length of stay and disposition also was recorded.

Complex Chronic Conditions

To determine whether admitted patients had ≥1 coexisting complex chronic condition (CCC), we used a previously published classification scheme that uses ICD-9-CM codes to classify pediatric chronic conditions into the following categories: neuromuscular, cardiovascular, respiratory, renal, gastrointestinal, hematologic and immunodeficiency, metabolic, other congenital or genetic defect, and malignancy.9

Statistical Analyses

Descriptive statistics were used to compare characteristics between VTE admissions and all hospital admissions and between patients with 1 VTE episode and those with recurrent VTE. The χ2 test was used for dichotomous and categorical variables (age, gender, race, ethnicity, disposition, and CCC), Student's t test was used compare the mean lengths of stay, and the Mann-Whitney test was used to compare the median lengths of stay. The rate of VTE was calculated by dividing the number of VTE admissions by the total number of hospital admissions. Poisson regression was used to model the rate of VTE in each age group and the use of anticoagulants over time. Linear regression was used to evaluate the effect of age on the use of enoxaparin and warfarin and to model the relationship between the rate of VTE and hospital size, with adjustment for year and hospital clustering. Stata 10.0 (Stata, College Station, TX) was used for all statistical analyses.

RESULTS

VTE Admissions

During the 7-year study period, there were a total of 13449 hospital admissions among 11337 pediatric patients with the diagnosis of VTE. Among the 13449 admissions, there were a total of 14917 ICD-9-CM codes for VTE; some patients received >1 VTE discharge code. These codes are grouped according to anatomic location in Table 1. Forty-one percent of VTE codes (6153 of 14 917 codes) were nonspecific ICD-9-CM codes. A diagnosis of pulmonary embolism occurred in 11% of VTE admissions (1434 of 13 449 admissions).

The demographic data for all hospital admissions and VTE admissions from 2001 to 2007 are listed in Table 2. Consistent with previously published studies, infants <1 year of age and teenagers accounted for the majority of VTE admissions.5, 8, 10 Fifty-five percent of the patients admitted with VTE were male, which was identical to the gender distribution for all admissions.

Patients admitted with VTE had longer hospitalizations, had a higher mortality rate, and were more likely to have a CCC than were patients without VTE (Table 2). The mean length of stay for all VTE admissions was 28 days, compared with only 6 days for all admissions. The mortality rate for patients for whom VTE was diagnosed was 8% (1030 of 13 449 patients), which was much higher than the 1% rate observed for hospital admissions during the time period. The majority (63%) of patients with VTE had ≥1 CCC, compared with 36% of all patients admitted. Among patients with VTE, a cardiovascular condition was the most common CCC (28%), followed by malignancy (14%) and neurovascular condition (11%) (Table 2).

Patients With VTE

Twelve percent of patients (1401 of 11 337 patients) had >1 admission with a diagnosis of VTE and were categorized as having recurrent VTE (Table 2). In comparison with those with only 1 admission for VTE, the proportion of patients with recurrent VTE was significantly lower among children <1 year of age (21% vs 36%; P < .001) and was significantly higher among teenagers (37% vs 27%; P < .001). Patients with recurrent VTE were more likely to have a CCC; most notably, the prevalence of malignancy among patients with recurrence was twice as high as that among patients without recurrence (24% vs 12%; P < .001).

VTE Admissions Over Time

The annual rate of VTE admissions increased 70% from 2001 to 2007 (from 34 to 58 cases per 10 000 hospital admissions; P < .001). This increase was observed in all age groups and is shown graphically in Fig 1. The rate increased 70% (from 44 to 75 cases per 10 000 admissions) among infants <28 days of age, 100% (from 25 to 50 cases per 10 000 admissions) among infants between 28 days and <1 year of age, 64% (from 25 to 41 cases per 10 000 admissions) among children 1 to <6 years of age, 52% (from 31 to 47 cases per 10 000 admissions) among children 6 to 12 years of age, and 49% (from 63 to 94 cases per 10 000 admissions) among teenagers 13 to 18 years of age.

Rates of VTE diagnosis according to age group, from 2001 to 2007. CI indicates confidence interval.

Hospital Size and Rate of VTE

There was significant interhospital variability in the rate of VTE admissions (Fig 2). After accounting for clustering (all hospitals were not included for the same number of years), there was a positive correlation between the annual number of admissions per hospital and the rate of VTE (P < .001) (Fig 2).

Anticoagulant Use

Enoxaparin was by far the most frequently prescribed low-molecular weight heparin in pediatric hospitals during this time period. The proportion of VTE admissions in which enoxaparin was used increased from 29% in 2001 to 49% in 2007 (P < .001), whereas the use of warfarin decreased slightly from 11% to 10% (P < .001) (Fig 3). The use of both anticoagulants increased with increasing age (Fig 4).

Use of anticoagulants according to age. CI indicates confidence interval.

It was not possible to distinguish between unfractionated heparin administered through continuous infusion for therapeutic anticoagulation and unfractionated heparin dispensed to flush or to maintain the patency of venous or arterial catheters. Therefore, we were unable to assess the proportion of patients who received unfractionated heparin as treatment for their VTE, and we were unable to determine the proportion of patients with VTE who underwent anticoagulation.

Additional Analyses

To confirm that the increase in VTE rate was not simply related to a temporal increase in diagnostic coding for VTE, we also searched for admissions in which enoxaparin was prescribed after 48 hours of admission. We added this exclusion to prevent the inclusion of patients who were being treated for a previous VTE episode. With the use of these criteria, there were an additional 6227 admissions, and the rate of enoxaparin use (for patients without an ICD-9-CM code for VTE) increased 114% from 2001 to 2007 (data not shown). Because some of those patients might have received enoxaparin for prophylaxis and not necessarily for the treatment of deep VTE, those admissions were not used to determine the rate of VTE.

DISCUSSION

This study demonstrates a significant steady increase in the diagnosis of VTE across all age groups in US children's hospitals from 2001 to 2007. The overall rate increase of 70% is substantial and confirms the observations of pediatric hematologists at single institutions.1–7 Neonates and adolescents had the highest rates of VTE, and the majority of patients had a CCC. The characteristics of patients with VTE in this study are similar to those reported for numerous smaller, prospective, pediatric VTE cohorts, adding confirmatory evidence regarding the validity of our findings.5, 8, 10

The only other study to examine the frequency of VTE over time among children in the United States used data from the National Hospital Discharge Survey (NHDS).11 That study estimated that the rate of VTE was 4.9 VTE cases per 100 000 children per year, and the rate did not change from the triennial periods of 1979–1982 to 1999–2001. The NHDS is designed to provide estimates of national hospitalization trends and overall disease burdens, but these estimates are generated from a relatively small proportion (∼1%) of all hospital discharges, and the hospitals that are sampled for the NHDS are short-stay, nonfederal hospitals and therefore are less likely to care for the pediatric patients with complex conditions in whom thrombosis most often occurs. We propose that, because the vast majority of children with VTE are treated in pediatric tertiary care hospitals, the NHDS study was unable to detect any change in the rate of VTE that might have occurred during that time.

Although our study includes data from the majority of tertiary care pediatric hospitals in the United States, it involves a limited sample, and undoubtedly many children with VTE were treated at other institutions. Therefore, it is not possible to estimate the incidence of VTE in the pediatric population, although we think that the increase in VTE admissions reflects an increase in the overall incidence of VTE in children. To argue otherwise would require that a significant proportion of neonates and children with VTE who previously were being treated at other institutions began receiving treatment in hospitals that contribute to the PHIS database. Given that the vast majority of children with VTE are likely to be treated in tertiary care hospitals and many regions in the United States are served by a limited number of such hospitals, this possibility is extremely unlikely.

Whether there has been a true increase in the occurrence of pediatric VTE, an increase in detection of previously undiagnosed VTE, or both cannot be determined from this study and clearly warrants further investigation. The complexity of the medical conditions of pediatric patients in tertiary care hospitals continues to increase, paralleling advances in therapeutics, technology, and supportive care. The presence of a central venous catheter is the single most common risk factor for VTE in children.5, 8, 10 We were unable to assess whether the VTE episodes in this study were related to catheters and whether an increase in the use of catheters during the study period could have explained the increase. Alternatively, perhaps an increase in the frequency and/or sensitivity of diagnostic imaging studies has resulted in the detection of previously undiagnosed VTE cases. It is also possible that heightened awareness of VTE in pediatric children's hospitals has contributed, particularly in larger centers with pediatric hematologists with expertise in thrombosis.

The use of enoxaparin for the treatment of VTE increased significantly throughout the 7-year period, whereas the use of warfarin decreased slightly. The use of either drug increased with age. The increase in enoxaparin use was not unexpected, because this is now often the drug of choice for the treatment of acute VTE in children.12 In contrast to unfractionated heparin, enoxaparin is administered subcutaneously (compared with continuous intravenous infusion) and usually is easier to titrate, with less monitoring. Despite this increase, enoxaparin was not used in more than one half (53%) of VTE admissions in 2007. Unfortunately, it was not possible to determine whether patients in those admissions received unfractionated heparin for treatment of their VTE or received no anticoagulant. As expected, the use of anticoagulants other than unfractionated heparin, warfarin, or enoxaparin, occurring in <1% of VTE admissions, is extremely rare in pediatrics.

Interestingly, there was a correlation between hospital size and VTE rates, such that larger hospitals tended to have higher rates of VTE. We hypothesize that larger hospitals may have larger proportions of critically ill children at higher risk of VTE or may be more likely to have a dedicated pediatric thrombosis specialist, which may lead to a higher index of suspicion and increased screening for VTE in those hospitals, for reasons similar to those described above.

A relatively significant proportion (13%) of patients had >1 admission with a diagnosis of VTE during the study period. Those patients tended to be older and were more likely to have a malignancy than were patients with only 1 VTE admission. These results should be interpreted with caution, because we were unable to verify that these were all recurrent events; it is possible that the previous VTE episode was included in the discharge codes for readmission. Furthermore, it is possible that patients went to other hospitals with recurrent VTE. However, the characteristics (proportion, older age, and association with malignancy) of this group are strikingly similar to those reported for pediatric patients with recurrent VTE in other cohorts, which supports this conclusion.10, 13

The primary limitation of our study is that we relied on ICD-9-CM codes for the diagnosis of VTE. In this administrative database, there is potential for misclassifying patients who have VTE but receive codes for alternative diagnoses, or vice versa. It is most likely, however, that we have underestimated the absolute rates of VTE among children in these hospitals, for 3 reasons. First, ICD-9-CM codes have been shown to be more specific than sensitive, underestimating the true frequency of conditions.14 Second, as we demonstrated, children with VTE often have complex medical conditions and prolonged hospitalizations, which can result in an extensive array of discharge diagnoses. Each patient in the PHIS database is limited to 21 ICD-9-CM discharge codes, and the diagnosis of VTE might not have been included in some cases. Third, there were an additional 6227 admissions in which enoxaparin was used for patients without an ICD-9-CM code for VTE, which was used as a surrogate indicator for cases of VTE. Although we did not include these patients in our analysis, it is likely that many were being treated for VTE, which suggests that we underestimated the true rate.

It is possible that the sensitivity of the abstractionists to identify and to code VTE accurately changed during the study period, such that patients with VTE were more likely to receive VTE codes in 2007 than in 2001. However, this would have needed to occur in nearly every hospital in the study, and there is no reason to suspect such systematic bias. In addition, by using pharmacy billing data, we were able to demonstrate that the use of enoxaparin increased to an even greater degree that ICD-9-CM–coded VTE, which supports our findings.

CONCLUSIONS

In pediatric tertiary care hospitals across the United States, VTE has become a rapidly growing problem. Pediatric hematologists faced with the challenge of caring for children with VTE must contend with the fact that most current treatment recommendations are extrapolated from adult studies.12 Studies directed at understanding the cause of this increase and determining optimal treatment strategies are essential for addressing this rapidly increasing condition.